Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741

Abstract

Novel approaches for the treatment of multidrug-resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed the in vitro efficacies of combinations of SPR741 with conventional antibiotics against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Of 35 antibiotics tested, the MICs of 8 of them were reduced 32-to 8,000-fold against E. coli and K. pneumoniae in the presence of SPR741. The eight antibiotics, azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and telithromycin, had diverse targets and mechanisms of action. Against A. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin, and rifampin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multidrug-resistant or clinical isolates of E. coli and K. pneumoniae and 17 additional A. baumannii isolates in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump in E. coli, effectively circumventing the contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.

Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae

“…Perhaps by increasing the rate of entry of these drugs into the cell through outer membrane permeabilization, colistin has the effect of producing an overall increase in the entry-to-exit ratio of antibiotics with which it acts in synergy. This accords with the finding that laboratory strains of Escherichia coli are modestly sensitized to linezolid by polymyxin derivative-induced membrane permeabilization, although not to nearly as marked a degree as by inactivation of the AcrAB-TolC efflux pump (29,32).…”

Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

“…These three antibiotics are not classical drugs used to treat Gram-negative bacillary infections due to intrinsic resistance, notably OM impermeability. At 2 g/ml of SPR741, the MIC 50 and MIC 90 of rifampin against a panel of MDR E. coli isolates were 0.016 and 0.06 g/ml, respectively (149). Rifampin alone has MIC 50 and MIC 90 values of 16 and Ͼ128 g/ml, respectively, against the same panel of E. coli strains (149).…”

“…In contrast to polymyxins, SPR741 has poor activity against Gram-negative pathogens on its own but can permeabilize the outer membrane to facilitate the entry of other antibiotics into the bacterial cell (147). For instance, SPR741 was reported to sensitize Enterobacteriaceae and A. baumannii but not P. aeruginosa to an extensive panel of antibiotics, including clarithromycin, fusidic acid, and rifampin (148)(149)(150). These three antibiotics are not classical drugs used to treat Gram-negative bacillary infections due to intrinsic resistance, notably OM impermeability.…”

Critical analysis of antibacterial agents in clinical development

“…Another polymyxin derivative (SPR741), with limited intrinsic activity but improved safety, is being studied for permeabilization of the outer membrane, thereby granting antibacterial agents access to their intracellular targets 93 . The most beneficial combinations of such a 'potentiator' strategy are not known yet, and development is pending.…”